Impact of HIV-1 Genotype on Therapy Response in Children

描述（由申请人提供）：长期目标是检查艾滋病毒感染儿童和青少年的艾滋病毒进化和免疫功能，这些儿童和青少年在开始含蛋白酶抑制剂的抗逆转录病毒治疗[ART]后，重建免疫[免疫成功，is]，但未能控制病毒复制[病毒失败，VF]。研究将集中在一个独特的队列治疗患者，他们持续免疫重建，尽管病毒载量可以预测疾病进展。这一结果组为病毒/宿主细胞相互作用的研究提供了一个新的范例，可能导致新的治疗策略。该提议的假设基础是art诱导的不协调反应是多因素的，涉及病毒的表型特性、胸腺的功能完整性以及正在进行的病毒复制对免疫的影响。为了确定VF/IS反应所涉及的机制，提出了三个具体目标：

DESCRIPTION (provided by applicant): The long-term objective is to examine HIV evolution and immune function in HIV-infected children and adolescents who, following initiation of protease inhibitor containing antiretroviral therapy [ART], reconstitute immunity [Immune success, IS] but fail to control viral replication [viral failure, VF]. Studies will focus on a unique cohort of treated patients who have sustained immune reconstitution in spite of viral loads that would predict disease progression. This outcome group presents a novel paradigm for the investigation of virus/host cell interactions that are likely to lead to novel new therapeutic strategies. The hypothesis underlying the proposal is that ART-induced discordant responses is multifactorial, involving phenotypic properties of the virus, functional integrity of the thymus, and the impact of ongoing viral replication on immunity. To determine the mechanisms involved in VF/IS responses, three specific aims are proposed: Specific Aim 1. To examine the evolutionary dynamics of amino acid substitutions in Gag and protease [PR] within the peripheral blood compartments of VF/IS individuals. Accumulation and modulation of genetic markers in Gag and PR amino acid sequences that develop in VF/IS individual during ART will be used to evaluate: [A.] compartmentalization of viruses in plasma and in CD4 CD45RO T lymphocytes and [B.] reservoirs of virus in CD4 CD45RA T lymphocytes. Specific Aim 2. To identify genetic determinants in gag and PR from VF/IS individuals that contribute preferentially to restricted replication in thymocytes. Recombinant viruses with gag/PR regions derived from discordant patients will be constructed and evaluated in culture to: [A.] compare pre- and post therapy gag/PR regions from viruses from VF/IS individuals with respect to their capacity to replicate in thymocytes and PBMC ex vivo and [B.] map genetic determinants in Gag and PR that contribute to preferential restriction of replicative capacity in thymocytes. Specific Aim 3. To determine the impact of ongoing viral replication on immunity among individuals who have discordant viral and immune outcomes. Specific studies will evaluate: [A.] thymic output, [B.] post thymic T cell activation and differentiation, and [C.] functional immune response to neoantigen between VS/IS and VF/IS outcome groups.